9-cis-RA 促进RXRα的SUMO化修饰增加MRP3表达减轻阻塞性黄疸肝损伤的机制

阻塞性黄疸（OJ）肝损伤增加了围手术期并发症和死亡率，探索其损伤机制和有效地治疗手段具有重要的临床意义。疏水性胆汁酸蓄积诱导ROS过度产生是阻黄肝损伤的重要病理机制。我们先前研究率先发现维生素A可以减轻阻黄时的氧化应激，改善肝功能。胆汁酸转运体MRP3有助于疏水性胆汁酸的排出，减轻肝损伤。预实验发现阻黄时MRP3代偿性表达增加但有时限性，维生素A代谢活性产物9-cis-RA可以促进MRP3的表达，同时抑制ROS的产生。9-cis-RA又是视黄酸核受体RXRα的配体，能通过SUMO修饰减少RXRα：RARα异二聚体的形成。RXRα：RARα异二聚体通过转录因子SP1可以抑制MRP3的表达。我们推测9-cis-RA通过以下通路抑制ROS的产生并改善肝功能：9-cis-RA→RXRα的SUMO修饰↑→RXRα：RARα异二聚体↓→SP1↑→MRP3↑→疏水性胆汁酸蓄积↓→ROS↓→肝损伤减轻。

Obstructive jaundice (OJ) liver damage increased perioperative complications and mortality, to explore the injury mechanism of OJ and effective treatment has important clinical significance. Excessive ROS induced by the accumulation of the hydrophobic bile acid is the important pathological mechanism of liver damage caused by OJ.Our previous study confirmed firstly that vitamin A could allevate oxidative stress during OJ, to improve the liver function. Multiple resisance drug protein 3(MRP3) contributes to accumulate the excretion of bile acid. It was shown by our preliminary experiments that compensatory expression of MRP3 is limited, 9-cis-RA, a metabolic product of vitamin A can promote the expression of MRP3 and inhibit the generation of ROS during OJ. Meanwhile 9-cis–RA is also the ligand of retinoic acid nuclear receptor alpha, could reduce RXR alpha: RAR alpha dimers formation by modifying the SUMO. RXR alpha: RAR alpha vision dimers can inhibit the expression of MRP3 via transcription factor SP1.So we propose a hypothesis that 9-cis-RA may promote SUMOylation of RXRα, reduce the formation of RXR alpha: RAR alpha, reduce the inhibition of SP1, stimulate the expression of MRP3, reduce the accumulation of bile acid and inhibit the generation of ros, attenuating liver injury.